Treatment for acute myeloid leukemia (AML) or myelodysplastic syndrome with a FLT3 mutation with gilteritinib or midostaurin in combination with chemotherapy.

Phase 1

• Conditions: Previously untreated Acute Myeloid Leukemia (AML) or Myelodysplastic syndromes with excess blasts-2 (MDS-EB2) with FLT3 mutations; MedDRA version: 20.0Level: LLTClassification code 10001941Term: AMLSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps); MedDRA version: 20.0Level: LLTClassification code 10068361Term: MDSSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps); Therapeutic area: Diseases [C] - Blood and lymphatic diseases [C15]

• Registration Number: EUCTR2018-000624-33-SE
• Lead Sponsor: HOVON Foundation

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Study Start: 2019-09-26
• Last Update Posted: 5 August 2024

Recruitment & Eligibility

• Status: ot Recruiting
• Sex: All
• Target Recruitment: 768

Inclusion Criteria

•Age =18 years
•Newly diagnosed AML or MDS with excess of blasts-2 (EB2) defined according to WHO criteria (appendix A), with centrally documented FLT3 gene mutation (either TKD or ITD or both). AML may be secondary to prior hematological disorders, including MDS, and/or therapy-related. Patients may have had previous treatment with erythropoiesis stimulating agents (ESA) for MDS. ESA have to be stopped at least four weeks before registration
•FLT3 mutation as assessed by DNA fragment analysis PCR for FLT3-ITD and FLT3-TKD mutation. Positivity is defined as a FLT3-ITD or FLT3-TKD / FLT3-WT ratio of = 0.05 (5%).
•Considered to be eligible for intensive chemotherapy
•Patient is suitable for oral administration of study drug
•WHO/ECOG performance status = 2
•Adequate hepatic function as evidenced by
oSerum total bilirubin = 2.5 × upper limit of normal (ULN) unless considered due to leukemic involvement following written approval by the (co) Principal Investigator
oAspartate aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP) = 3.0 × ULN, unless considered due to leukemic involvement following written approval by the (co) Principal Investigator
•Adequate renal function as defined by creatinine clearance > 40 mL/min based on the Cockroft-Gault glomerular filtration rate (GFR)
•Written informed consent
•Patient is capable of giving informed consent
•Female patient must either:
oBe of nonchildbearing potential:
?Postmenopausal (defined as at least 1 year without any menses) prior to screening, or
?Documented surgically sterile or status posthysterectomy (at least 1 month prior to screening)
oOr, if of childbearing potential,
?Agree not to try to become pregnant during the study and for 6 months after the final study drug administration
?And have a negative urine or serum pregnancy test at screening
?And, if heterosexually active, agree to consistently use highly effective* contraception per locally accepted standards in addition to a barrier method starting at screening and throughout the study period and for 6 months after the final study drug administration.
*Highly effective forms of birth control include:
•Consistent and correct usage of established hormonal contraceptives that inhibit ovulation,
•Established intrauterine device (IUD) or intrauterine system (IUS),
•Bilateral tubal occlusion,
•Vasectomy (A vasectomy is a highly effective contraception method provided the absence of sperm has been confirmed. If not, an additional highly effective method of contraception should be used.)
•Male is sterile due to a bilateral orchiectomy.
•Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual activity during the entire period of risk associated with the study drug. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical study and the preferred and usual lifestyle of the patient.
*List is not all inclusive. Prior to enrollment, the investigator is responsible for confirming patient will utilize highly effective forms of birth control per the requirements of the CTFG Guidance document 'Recommendations related to contraception and pregnancy testing in clinical trials' during the protocol defined period.
oFemale patient must agree not to breastfeed starting at screening and throughout the study period, and for 2 months and 1 week after the final study drug administration.
oFemale patient must not dona

Exclusion Criteria

•Prior chemotherapy for AML or MDS-EB2, including prior treatment with hypomethylating agents. Hydroxyurea is allowed for the control of peripheral leukemic blasts in patients with leukocytosis (e.g., white blood cell [WBC] counts > 30 x 109/L)
•Acute promyelocytic leukemia (APL) with PML-RARA or one of the other pathognomonic variant fusion genes/chromosome translocations
•Blast crisis after CML
•Known or suspected hypersensitivity to midostaurin or gilteritinib and/or any excipients
•Patient requires treatment with concomitant drugs that are strong inducers of cytochrome P450 (CYP) 3A
•Breast feeding at start of study treatment
•Active infection, including hepatitis B or C or HIV infection that is uncontrolled at randomization. An infection controlled with an approved or closely monitored antibiotic/antiviral/antifungal treatment is allowed.
•Patients with a currently active second malignancy. Patients are not considered to have a currently active malignancy if they have completed therapy and are considered by their physician to be at less than 30% risk of relapse within one year. However, patients with the following history/concurrent conditions are allowed:
oBasal or squamous cell carcinoma of the skin;
oCarcinoma in situ of the cervix;
oCarcinoma in situ of the breast;
oIncidental histologic finding of prostate cancer
•Significant active cardiac disease within 6 months prior to the start of study treatment, including:
oNew York Heart Association (NYHA) Class III or IV congestive heart failure;
oMyocardial infarction;
oUnstable angina and/or stroke;
oLeft ventricular ejection fraction (LVEF) < 40% by ECHO or MUGA scan obtained within 28 days prior to the start of study treatment
•QTc interval using Fridericia’s formula (QTcF) = 450 msec (average of triplicate determinations) or other factors that increase the risk of QT prolongation or arrhythmic events (e.g., heart failure, family history of long QT interval syndrome). Prolonged QTc interval associated with bundle branch block or pacemaking is permitted with written approval of the (co) Principal Investigator.
•Patient with hypokalemia and/or hypomagnesemia before registration (defined as values below LLN) Note: electrolyte suppletion is allowed to correct LLN values before registration.
•Dysphagia, short-gut syndrome, gastroparesis, or other conditions that limit the ingestion or gastrointestinal absorption of orally administered drugs
•Clinical symptoms suggestive of active central nervous system (CNS) leukemia or known CNS leukemia. Evaluation of cerebrospinal fluid (CSF) during screening is only required if there is a clinical suspicion of CNS involvement by leukemia during screening
•Immediate life-threatening, severe complications of leukemia such as uncontrolled bleeding and/or disseminated intravascular coagulation
•Any other medical or psychological condition deemed by the Investigator to be likely to interfere with a patient’s ability to give informed consent or participate in the study
•Any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified